Etiologies of Chronic Prostatitis

1. Introduction
2. Histopathological Aspects of Chronic Prostatitis
3. Microbiological Aspects of Chronic Prostatitis
4. Immunological Aspects of Chronic Prostatitis
5. Chemical Aspects of Chronic Prostatitis
6. Urodynamic and Myalgic Aspects of Chronic Prostatitis
7. Psychological Aspects of Chronic Prostatitis
8. Reproductive Aspects of Chronic Prostatitis

Introduction

It is estimated that in the United States today anywhere between 15-20% of all urology patient visits are for chronic prostatitis. The most common urology diagnosis for American males under age 50 is chronic prostatitis. Above age 50, on insurance claims the frequency of chronic prostatitis is outnumbered by benign prostatic hypertrophy (BPH). About two decades later a third peak shows up, prostate cancer. During my ten year career as a general pathologist, while examining tissue samples from prostates that were surgically removed or prostate biopsies with a diagnosis of benign prostatic hypertrophy, I saw evidence of chronic or acute inflammatory cell invasion in every case. Similarly, the tissue samples I examined that were taken from prostate glands with documented cancerous changes without exception always revealed inflammatory changes. 

Histopathological aspects of prostatitis

I believe that both benign and cancerous changes in the prostate develop on an infectious background.  It is therefore pointless to argue about the true prevalence of histologically confirmed prostatitis in the absence of other prostatic disease.  Uninfected prostate tissue is not altered by hyperplasia or cancerous processes. These late changes do not contribute to the development of inflammatory signs, they are caused by the inflammation. The prevalence of inflammation in benign or malignant prostate diseases is reported to be up 100% of cases.

The basic definition characterizing the process of acute prostatitis is the presence of polymorphonuclear leukocytes (PMNL) and macrophages in the glandular ducts, the epithelium and/or the adjacent stroma. As the disease becomes chronic, stromal involvement varies, and increases with the density of intraluminal inflammation. Periglandular accumulation of lymphocytes and monocytes, and occasionally plasma cells characterize the chronic phase of the infection. The inflammation starts from the central periurethral zone and spreads to the  peripheral zone.

There is little or no correlation between the histological presence of chronic prostatitis and the clinical symptoms. The histological signs of chronic prostatitis also include distortion of the glandular ducts, disruption of the epithelium, atrophy and loss of the secretory activity of the epithelium, and hyperchromasia with polymorphism of the epithelial cell nuclei and cytoplasmic basophilia. These dysplastic changes can be misinterpreted as carcinoma of the prostate if the association with chronic prostatitis is not recognized. The situation can be worsened by changes such as squamous metaplasia, which occurs frequently in the inflamed areas of chronic prostatitis.

A fine-needle aspiration (FNA) method was developed to gage the type and extent of inflammation, but it is contraindicated in cases of acute symptomatic prostatitis due to the risk of sepsis, especially in patients with suppressed immune system.

The most common changes observed in chronic prostatitis are glandular atrophy with stromal fibrosis, accompanied by a mild residual inflammation reaction occurring in several stages. Epithelial changes are frequent, ranging from squamous metaplasia to dysplastic changes.

We believe that acute prostatitis leading to chronic prostatitis resulting in prostate cancer is a continuum of an evolving disease process. I never fail to remind my patients that it is not age that will predispose them to an enlarging prostate and prostate cancer but, rather the microorganisms that enter the prostate during the preceding decades. Hystologically, acute or chronic prostatitis is defined based on the predominant inflammatory cells observed in the histology.

  

Microbiological aspects of prostatitis

It is essential to be able to demonstrate bacteria reliably in the EPS, semen or both in order to reach the correct treatment decisions and to ensure a good outcome. Laboratory findings have shown in practice that almost all standard localization cultures are negative and that success in culturing bacteria from EPS is complicated by the presence of inhibitory substances known to exist in prostate secretion and by a history of multiple previous courses of antibiotics. Clear confirmation of the pathogenicity of bacteria in prostate tissue and/or ducts has been obtained with a group of gram-negative uropathogens including E. coli, Klebsiella spp., Serratia and Pseudomonas spp. There can also sometimes be gram-positive uropathogens such as Enterococcus spp. and Staphylococcus spp. present.

While acute prostatitis is characterized by polymorphonuclear leukocytic infiltration, the chronic phase of infection in chronic prostatitis is characterized by lymphocytic infiltrate. The degree of infiltration is not proportional to the clinical symptoms. The adjacent edema/collagen tissue formation depends on the nature of the bacteria, the host reaction to the infection, and the duration of the process. While mostly edema is seen in acute prostatitis, as the disease becomes chronic, fibrous collagen tissue will replace the prostatic tissues and later, nodular or symmetrical enlargement of the prostate will take place. Since the dawn of microbiology, repeated attempts have been made to isolate bacteria believed to be the cause of chronic prostatitis.

A number of studies implicate specific groups of bacteria but for one reason or another these studies are mostly inconclusive. Whether it was the sample size or the narrow spectrum of bacteria tested, the most these studies were able to establish was an association of a specific bacterium with prostatitis. Both gram negative and gram-positive bacteria have been implicated and are believed to be uropathogens. The anaerobic studies in most instances are hampered by the notorious difficulty encountered in isolating anaerobic bacteria. A number of studies implicate Ureaplasma/Mycoplasma as causative organisms. The same bacteria believed to cause acute prostatitis, if incorrectly treated, will become the cause for chronic bacterial prostatitis. I will list these bacteria when dealing with acute prostatitis.

Chlamydia trachomatis has been studied and implicated in a number of studies as well. As I mentioned before, in our clinic over 60% of patients presenting with the diagnosis of chronic prostatitis will reveal elementary bodies of Chlamydia in the smear prepared from a urethral swab. We use the fluorescence antibody technique to identify the elementary bodies. The antiserum is produced in animals and I believe it is more sensitive in detecting the  elementary bodies of Chlamydia than the widely used PCR or nucleic acid amplification technique. My belief stems from the simple observation that after a relatively short antibiotic course, PCR tests can rapidly turn negative while the fluorescence antibody test will still reveal elementary bodies. A persistent positive reading with the antibody test is in synchrony with the clinical course and it turns negative following the resolution of the clinical symptoms. It has been documented that an amplification test used in certain parts of Sweden was unable to identify Chlamydia. Its inability to identify Chlamydia was not due to an actual drop of newly infected cases but rather to Chlamydia’s ability to change its surface antigens targeted by the testing kit. Since the fluorescence antiserum is produced in animals the host is likely to produce antibodies against many surface markers of Chlamydia, thus making the fluorescence antibody technique the gold standard for detecting Chlamydia infection.Unfortunately the test requires an expert to read it, and it is time consuming.

We believe that the most common cause of chronic prostatitis is a Chlamydia infection that is hardly ever treated properly at the time of the first visit.

The clinical course of chronic prostatitis cannot be explained well without recalling the lifecycle of Chlamydia trachomatis. The quick response to relatively short courses of antibiotic therapy at the beginning of the infection only eliminates those extracellular elementary bodies that are sensitive to that particular antibiotic. The relatively quick recurrence of the infectious symptoms is best explained by either the fact that bacteria that were not sensitive to the original antibiotic are now selected out and start multiplying even before the first course of antibiotic is finished. The second time around,  therefore there is no symptomatic improvement from the same antibiotic,  even if longer courses are prescribed. The second reason is that most prescribed antibiotics will only affect the extra cellular phase of bacterial growth. The intracellular multiplication and emergence of the reticulate bodies, after a symptom free period of varying length can cause recurring symptoms long after the initial antibiotic therapy is completed.Chlamydia is known to change its antibiotic sensitivity and it will alter its growth rate after exposure to multiple antibiotics. Also, the state of the immune system and host of other factors can influence the effect of Chlamydia on the host’s tissues. As the growth rate of the intracellular forms of Chlamydia diminishes and eventually spore forms develop, the time interval between reoccurrences widens. Chlamydia is uniquely suitable to interact with intracellular nucleotides, thus, as it has been associated with increased female cervical cancer risk,it would not be an unreasonable speculation to associate chronic Chlamydia infection with the development of prostate cancer.

It is good to remember that Chlamydia trachomatis is not one bacterium.  Within the family an infinite variety of different sub species can be found.  These bacteria differ not only in their size and multiplication rate but they can have different pathogenic potential, including different interaction with the immune system, different antibiotic sensitivity, different speed in developing resistance to antibiotics and different ways of coexisting, irritating or destroying the tissues they infect.

The clinical course of chronic prostatitis cannot be explained well without recalling the lifecycle of Chlamydia trachomatis. The quick response to relatively short courses of antibiotic therapy at the beginning of the infection only eliminates those extracellular elementary bodies that are sensitive to that particular antibiotic. The relatively quick recurrence of the infectious symptoms is best explained by either the fact that bacteria that were not sensitive to the original antibiotic are now selected out and start multiplying even before the first course of antibiotic is finished. The second time around. Therefore there is no symptomatic improvement from the same antibiotic,  even if longer courses are prescribed. The second reason is that most prescribed antibiotics will only affect the extra cellular phase of bacterial growth. The intracellular multiplication and emergence of the reticulate bodies, after a symptom free period of varying length can cause recurring symptoms long after the initial antibiotic therapy is completed.

Chlamydia is known to change its antibiotic sensitivity and it will alter its growth rate after exposure to multiple antibiotics. Also, the state of the immune system and host of other factors can influence the effect of Chlamydia on the host’s tissues. As the growth rate of the intracellular forms of Chlamydia diminishes and eventually spore forms develop, the time interval between reoccurrences widens. Chlamydia is uniquely suitable to interact with intracellular nucleotides, thus, as it has been associated with increased female cervical cancer risk, it would not be an unreasonable speculation to associate chronic Chlamydia infection with the development of prostate cancer.

It is good to remember that Chlamydia trachomatis is not one bacterium.  Within the family an infinite variety of different sub species can be found.  These bacteria differ not only in their size and multiplication rate but they can have different pathogenic potential, including different interaction with the immune system, different antibiotic sensitivity, different speed in developing resistance to antibiotics and different ways of coexisting, irritating or destroying the tissues they infect.

Possible temporary pathogens in prostate tissue and/or ducts under certain conditions can be: coagulase-negative Staphylococcus species, Chlamydia, Ureaplasma, Candida and Trichomonas.

Acknowledged not to be pathogens so far are: Diphteroids, Lactobacilli and Corynebacteria spp.

Last but not least, we must also mention cryptic non-culturable organisms such as altered ”biofilm-forming colonies”, viruses and cell-wall-deficient bacteria, the importance of which for the immune system of the host is not completely understood.

Immunological Aspects of Chronic Prostatitis

The secretory immune response is an essential factor in helping the mucosal barrier to resist bacterial invasion into the glandular-epithelial system of the prostate gland. The prostate secretes local antibodies in response to infection or to the remnants of bacterial protein, and this local response is often different from the systemic one reflected in the serum findings. The amounts of immunoglobulins G and A (IgG and IgA) have been found to be much lower in normal human prostatic fluid than in patients with prostatitis. It thus appears that measurements of antigen-specific IgA and IgG levels in the prostatic fluid can be helpful in the diagnosis of prostatitis and in determining the possible response to long-term courses of antibiotics in patients with a confirmed etiology.

The most common aetiological factor having a strong immunological effect on the secretion of antigen-specific IgA into the prostatic fluid, independent of the systemic immune response, is E. coli (Wishnow et al. 1982). Occasionally certain enterococcus species and certain staphylococci can initiate strong IgA production.

Typical over-reactions of the host response and delayed hypersensitivity reactions are represented by inflammatory infiltrates from T-lymphocytes (CD4+ T helper/inducer cells and CD8+ T cytotoxic/suppressor cells), which are distributed variously between the epithelial and stromal components. This can be due to intraprostatic spermatozoa intrusion, which is known to have a powerful autoimmunization capacity and activity in some cases.

Chemical Aspects of Chronic Prostatitis

The chemical composition of expressed prostatic secretion (EPS) and urine of patients with chronic prostatitis often, show that the origin of the chemical reaction and the basis for tissue inflammation was reflux into the prostatic ducts.

If prostatic ducts are obstructed by calculi, there may be a mechanical reaction on the epithelia through rising intraductal fluid pressure or direct irritation from calculi.

We propose that infection in the prostate is the primary event causing anatomical structural changes, and functional disorders, like reflux, comes later. Chronic inflammation, upon which local tissue reactions, tissue edema with increased intracompartmental tissue pressure develops, leads to voiding disturbances with more reflux of urine, sterile or infected.

Urodynamic and Myalgic Aspects of Chronic Prostatitis

Measurement of urine flow rate could be justified in the evaluation of prostatitis patients, with prostatodynia.

In the later stages of chronic prostatitis  “painful urethral syndrome” can develop due to Increased pressure in the prostatic urethra caused by the advancing scarring. This condition will lead to reflux into the prostatic ducts and ejaculatory ducts accompanied by painful prostate tissue irritation (chemical reaction of urine component, seminal vesiculitis and even epididymitis in cases of infected urine). It is appropriate to perform video-urodynamic assessment to rule out possible neurological reasons for voiding disturbances. and/or to validate any findings of organic causes.

Some patients with CP/CPPS appear to suffer mainly from tension myalgia of the pelvic floor. Patients also report pain and discomfort associated with sitting, running or other physical activities that lead to spasms in the perineal muscles. Most of these patients suffer from a combination of prostatitis and seminal vesiculitis.

Psychological Aspects of Chronic Prostatitis Prostatitis

Sexual neurasthenia can occur in a small but very definitive group of prostatitis patients in association with maritual difficulties, melancholia, nervousness, irritability, depression and also suicidal tendencies. Psychological factors are considered by some to play an important role in the aetiology of chronic prostatitis.

Urological patients with chronic complaints generally tend to exhibit psychiatric problems, and there is a widely held belief among urologists, that these patients are ”neurotic”. In this view chronic prostatitis patients often tend to be characterized as having problems with their male sexual identity. Symptoms such as anxiety, depression, fear, sexual disturbances and feelings of insecurity in human relationships have been reported. Psychosomatic factors were found to be important aspects in connection with a ”psychosomatic personality” and in the expression of psychological emotional problems as a whole. Patients have reported that their symptoms greatly affect sexual or romantic relationships.

Psychological evaluation, relationship counseling and even medical treatment for depression may play an important role in the overall approach to chronic prostatitis patients.

Reproductive Aspects of Chronic Prostatitis

Finally, I would like to mention that chronic prostatitis has a significant role in infertility. It can not only affect the fertilizing capacity of spermatozoa but recurring stubborn Chlamydia infections can cause a wide-spectrum of fertility problems and infectious symptoms in the partners of males who have ongoing chronic prostatitis. the photograph here shows a dilated prostatic duct from a biopsy specimen of a patient with chronic prostatitis. Note the cluster of inflammatory cells and bacteria within the lumen. These bacteria find their way into the ejaculate and ultimately become the cause of infections within the female tract.  Figure 1